Alzheimer?s disease and related dementias (AD/ADRD) are neurodegenerative disorders that are clinically characterized by progressive dementia and spatial disorientation caused in part by proteotoxicity and neuronal death. The pathogenic mechanisms causing AD/ADRD have remained elusive, which has led to alternative hypotheses that defects in central and systemic glucose metabolism and type 2 diabetes are potential risk factors for proteostasis failure and cognitive decline. There is currently no evidence to support a cause or effect relationship between AD/ADRD and metabolic dysfunction/insulin resistance. Macroautophagy (MA) is a key homeostatic mechanism that protects against neurogenerative disorders. MA also prevents type 2 diabetes through its effects in both the central nervous system (CNS) and peripheral tissues. The role of MA is well-defined in the mediobasal hypothalamic (MBH) neurons in the CNS in preventing obesity and insulin resistance. Since AD-related proteotoxicity and aging each overwhelms MA function, and because hypothalamic MA maintains glucose and energy metabolism, we hypothesized that an early event in AD- related proteotoxicity is disruption of MA in MBH and peripheral tissues, which results in systemic insulin resistance that in turn, accelerates the progression of AD/ADRD. We recently demonstrated that a novel isocaloric twice-a-day (ITAD) feeding strategy provides system-wide metabolic benefits by stimulating MA. Consequently, we propose that ITAD feeding will restore MA and metabolic function and delay cognitive impairment in AD/ADRD. To that purpose, we will collaborate with other components of this PPG and: (1) determine the impact of AD-related proteotoxicity on MA and regulation of metabolism in peripheral tissues as a function of nutritional stress and aging; (2) determine whether metabolic defects in models of AD-related proteotoxicity originate from compromised hypothalamic MA; and (3) explore whether ITAD feeding activates MA and prevents metabolic and cognitive defects in AD-related proteotoxicity. Integration in the PPG: In this project, we will use three complementary mouse models of AD-related proteotoxicity and AD/ADRD at distinct age groups that will be generated by the Animal Core and tissues will be shared by all projects. Assessments of metabolism and mechanisms of loss of MA in models of AD-related proteotoxicity and in response to dietary stress and age will be determined in collaboration with P1. Image- based assessments of the changes in MA in MBH and peripheral tissues will be done with the Imaging Core. Characterization of inflammatory changes in peripheral tissues in models of proteotoxicity will be performed in collaboration with P2 and P3. Analyses and integration of data will be carried out with the help of the Biostatistics and Data Management Core. Relevance to public health: Experiments proposed in P4 will test a new hypothesis that development of diabetes, as a consequence of MA failure in models of AD-related proteotoxicity and AD/ADRD, is a major contributing factor to the progression of disease. This project may also reveal that a simple, relatively cost- effective, and immediately translatable approach, ITAD feeding, can delay cognitive failure and extend healthspan in AD/ADRD patients by restoring MA and improving proteostasis.